Among the obstacles to successful breast cancer chemotherapy, three have been critical: problems of drug delivery, drug resistance, and cancer stem cells (CSCs). Until now, no effort has been made to address all three issues in a single approach. This proposal seeks to meet the challenge through a nanoplatform that we recently developed, which is comprised of a human serum albumin (HSA) coating, an amine-rich intermediate coating, and an iron oxide nanoparticle (lONP) core. It structurally resembles Abraxane, a commercial paclitaxel-HSA complex, but has smaller hydrodynamic size therefore better tumor accumulation rate and extravasation rate. Such favorable pharmacokinetics can be further improved by adding an external field at the tumor sites, making the nanoplatform a promising drug delivery vehicle. With superior ligand binding capability afforded by both the outer HSA and intermediate amine-rich layers, such nanoplatform can load a broad range of drug molecules. In this proposal, we plan to load such a nanoplatform with doxorubicin (or paclitaxel), salinomycin and tariquidar (or siRNA that targets the MDR-1 gene). Doxorubicin (or paclitaxel) is a chemotherapeutic agent that is commonly used in breast cancer therapy, directed toward killing the differentiated tumor cells that account for most of a tumor mass. Salinomycin is a recently identified therapeutic agent with selective CSC killing capability. Both tariquidar and siRNA can function as MDR-1 inhibitors and their modulating effects may lead to increased drug accumulation. It is hoped that, with complementary cancer killing mechanisms and favorable tumor targeting profile provided by the nanoplatform, this novel approach may lead to dramatically improved therapeutic effects. This will be the first investigation on tumor therapy to address problems of drug delivery, drug resistance, and CSCs in a single approach. Success of this study may be a milestone in breast cancer therapy for providing a powerful, all-inone, breast cancer therapeutic regimen.